Alzheimer's disease is a widespread progressive dementia affecting a significant fraction of the elderly population. While there have been significant advances in the research over about the last five years, the primary pathology of the disorder remains unknown. The behavioral symptoms of Alzheimer's disease are well known, and include loss of memory and cognitive function. The salient pathological symptom of Alzheimer's disease at autopsy is the presence in certain brain areas of extracellular proteinaceous deposits or plaques called amyloid on the basis of their staining with various reagents.
The extracellular amyloid is deposited both at neuronal and vascular sites, and the density of these deposits in the cerebral cortex and blood vessels correlates positively with the degree of dementia (D. J. Selkoe, Neuron 6:487 (1991); D. J. Selkoe Science 248:1058 (1990); B. Muller-Hill et al., Ann Rev. Biochem. 58:287 (1989); R. Katzman et al., FASEB J. 5:278 (1991)). The principal component of both neuritic and vascular plaques in Alzheimer's disease is beta-amyloid peptide (.beta.-amyloid or A4 peptide), a hydrophobic peptide of 39-43 amino acids which is encoded by a gene for a much larger protein termed the amyloid precursor protein (APP). Mature amyloid plaques have a halo of degenerating neurons around a core of the .beta.-amyloid peptide (R. J. Perry, Br. Med. Bull. 42:34-41 (1986). To date, neither the processing of APP to .beta.-amyloid peptide nor the genesis of the amyloid deposits has been well understood. The characteristics of .beta.-amyloid peptide deposition and the factors that affect it remain key questions in the pathology of Alzheimer's disease.
At the present time, there is no established test other than brain biopsy for diagnosing Alzheimer's disease antemortem. Further, there is no system to quantify neuropathological changes associated with Alzheimer's disease. In addition, there is no method that has been developed to screen and evaluate agents that may have unique anti-Alzheimer's disease action. There is also no method for in vitro evaluation of anti-Alzheimer's disease agents that does not require a sample of patient tissue.
In view of the present lack of knowledge about the development and progression of Alzheimer's disease, there is a need for agents and methods suitable for the diagnosis and detection of Alzheimer's disease. More particularly, there is a need for compounds and assay techniques that can be employed to screen for potential agents that inhibit or enhance the development of amyloid plaques. Such compounds and methods would be useful in assessing senile plaque formation associated with the onset and progression of Alzheimer's disease.